Abstract
Cocaine use disorder remains a persistent public health dilemma that currently lacks effective treatment strategies. One key impediment to successful treatment outcomes is increased drug craving that occurs over the course of abstinence and subsequent relapse to drug use. This phenomenon, known as the incubation of drug craving, has been modeled extensively in rodent models of intravenous drug self-administration. As commonly implemented, the design of intravenous self-administration preclinical studies precludes disentangling appetitive and consummatory behaviors as drug seeking (appetitive) and taking (consummatory) is simultaneous. Here, we employed a model of oral cocaine self-administration to interrogate the incubation of drug vs nondrug craving, where the route of administration is identical between reinforcers and appetitive and consummatory behaviors are dissociable. Oral self-administration of cocaine produced detectable levels of cocaine and its metabolite, benzoylecgonine, within the blood and brain, and blood and brain levels of both substrates correlated with cocaine consumption. When tested for seeking- (lever pressing) and taking-related (magazine head entries) behavior after 1 or 21 days of forced abstinence from cocaine or saccharin, we observed incubation of lever pressing among cocaine-administering mice and incubation of magazine entries among saccharin-administering mice. These behavioral changes were accompanied by reduced expression of the glial glutamate transporter GLT-1 within the nucleus accumbens (NAc) of cocaine self-administering mice, regardless of abstinence. Altogether, these results underscore the utility of this model of cocaine self-administration, highlight the conserved nature of incubated cocaine seeking across routes of administration, and demonstrate the dissociable neurobehavioral sequelae of the incubation of reward seeking across reinforcer types.